Iontophoresis device

ABSTRACT

The present invention provides an iontophoresis device with high administration efficient of a drug. An iontophoresis device, including an active electrode structure including: an electrode to which a positive electrical potential is applied; a drug holding part for holding a drug solution containing positively charged drug ions, the drug holding part being placed on a front side of the electrode; a cellulose-based resin film placed on a front side of the drug holding part or a complex film composed of a cation exchange membrane and a cellulose-based resin film placed on a front side of the cation exchange membrane, the complex film being placed on a front side of the drug holding part, in which the drug ions are administered through the cellulose-based resin film.

CROSS-REFERENCE TO RELATED APPLICATION

This application is a continuation of U.S. patent application Ser. No.11/195,364, filed Aug. 2, 2005, now pending, which application isincorporated herein by reference in its entirety.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present disclosure relates to an iontophoresis device foradministering positively charged drug ions to a living body by an actionof a positive electrical potential applied to an active electrodestructure holding the drug ions.

2. Description of the Related Art

An iontophoresis device generally includes an active electrode structureholding a drug solution whose active ingredient is dissociated topositive or negative ions (drug ions) and a counter electrode structurethat functions as a counter electrode of the active electrode structure.The drug ions are administered to a living body by the application of anelectrical potential or voltage with the same polarity as that of thedrug ions to the active electrode structure under the condition thatboth the assemblies are in contact with a biological interface (e.g.,skin, mucus membrane) of the living body (e.g., human being or animal).

The charge supplied to the active electrode structure is consumed by themovement of the drug ions to the living body and the release ofbiological counter ions present in the living body and having a polarityopposite to that of the drug ions) to the active electrode structure.The biological counter ions typically released are those having a smallmolecular weight (e.g., Na⁺ and Cl⁻) and hence high mobility. Therefore,the transport number (i.e., ratio of the amount of current contributingto the movement of the drug ions among the whole current supplied to theactive electrode structure) decreases, which makes it difficult orimpossible to administer a sufficient amount of drug.

JP 3030517 B, JP 2000-229128 A, JP 2000-229129 A, JP 2000-237326 A, JP2000-237327 A, JP 2000-237328 A, JP 2000-237329 A, JP 2000-288097 A, JP2000-288098 A and WO 03/037425 disclose iontophoresis devices thatattempt to solve the above-mentioned problem.

More specifically, in each of the iontophoresis devices described in theabove-cited references, an active electrode structure is composed of anelectrode, a drug holding part placed on a front side (i.e., a sidefacing to the biological interface when in use) of the electrode, and anion-exchange membrane that is placed on a front side of the drug holdingpart and selectively passes ions with the same polarity as that of thedrug ions held by the drug holding part, and the drug ions areadministered through the ion-exchange membrane, whereby the release ofbiological counter ions is suppressed in an effort to enhance thetransport number and thus the administration efficiency of the drug.

In the iontophoresis devices in the above-cited references, the activeelectrode structure further includes an electrolyte solution holdingpart for holding an electrolyte solution in contact with the electrode,and an ion-exchange membrane that is placed on a front side of theelectrolyte solution holding part that selectively passes ions having apolarity opposite to that of the polarity of the drug ions, and the drugholding part is placed on a front side of the ion-exchange membrane, inan effort to prevent the drug ions from being decomposed, by isolatingthe drug ions from the electrode and preventing the movement of H⁺ orOH⁻ ions generated at the electrode to the drug holding part and thebiological interface of a living body.

Furthermore, JP 2004-188188 A discloses a purported improvement over theiontophoresis devices disclosed in JP 3030517 B, JP 2000-229128 A, JP2000-229129 A, JP 2000-237326 A, JP 2000-237327 A, JP 2000-237328 A, JP2000-237329 A, JP 2000-288097 A, JP 2000-288098 A and WO 03/037425. JP2004-188188 A teaches that the administration amount of a drug can beenhanced remarkably by using an ion-exchange membrane in which a porousfilm composed of a material such as polyolefin, vinyl chloride resin, orfluorine resin is filled with an ion-exchange resin (a resin providingan ion-exchange function).

As described above, the iontophoresis device disclosed in JP 2004-188188A is purported to be the one having the most excellent administrationefficiency of a drug among those which are known at present. However,further improvements with respect to administration efficiency of drugdelivery are desirable, even as compared with the iontophoresis devicedisclosed in JP 2004-188188A.

BRIEF SUMMARY OF THE INVENTION

In one aspect, an iontophoresis device for administering positivelycharged drug ions includes an active electrode structure having anelectrode to which a positive electrical potential or voltage isapplied, a drug holding part for holding a drug solution containing drugions, the drug holding part being placed on a front side of theelectrode, and a cellulose-based resin film placed on a front side ofthe drug holding part.

For example, an iontophoresis device for administering a drug whoseactive ingredient is dissociated to positive ions in a solution, mayemploy a cellulose-based resin film in place of the ion-exchanged filmplaced on a front side of the drug holding part in each of theiontophoresis devices of JP 3030517 B, JP 2000-229128 A, JP 2000-229129A, JP 2000-237326 A, JP 2000-237327 A, JP 2000-237328 A, JP 2000-237329A, JP 2000-288097 A, JP 2000-288098 A, WO 03/037425 and JP 2004-188188A.

The cellulose-based resin film functions as a cation exchange membrane.However, the characteristics such as an ion-exchangeability of thecellulose-based resin film are inferior to those of generally usedcation exchange membranes (e.g., those illustrated in JP 3030517 B, JP2000-229128 A, JP 2000-229129 A, JP 2000-237326 A, JP 2000-237327 A, JP2000-237328 A, JP 2000-237329 A, JP 2000-288097 A, JP 2000-288098 A, WO03/037425 and JP 2004-188188 A). Accordingly, it has been out ofconsideration for those skilled in the art to apply the cellulose-basedresin film to the iontophoresis device.

In fact, in the study by the inventors of the present subject matter,the characteristics superior to those of the other cation exchangemembranes have not been confirmed in vitro evaluation, which isgenerally performed in an initial stage of development. However, whenevaluation was performed in vivo using a living body, it has been foundthat, according to the above-mentioned iontophoresis device of thepresent disclosure, the administration efficiency of a drug (i.e., drugadministration amount per unit time under the same current conditionsfrom a film surface with the same surface area) is remarkably enhanced,compared with the iontophoresis device using a cation exchange resindisclosed in JP 2004-188188 A.

Herein, examples of the drug whose active ingredient is dissociated topositive ions may include: an anesthetic agent such as morphinehydrochloride or lidocaine; a gastrointestinal disease therapeutic agentsuch as carnitine chloride; and a skeletal muscle relaxant such aspancuronium bromide.

In another aspect, the drug holding part of the active electrodestructure can be configured as a container for holding theabove-mentioned drug solution in a liquid state. The drug holding partmay hold the drug solution in a gelled or gelatinized form with anappropriate gelling agent. Alternatively, a polymer carrier or the likeimpregnated with a drug solution may be used as the drug holding part.

The cellulose-based resin film may take the form of a thin film composedof a cellulose-based resin such as regenerated cellulose, celluloseester, cellulose ether, or cellulose nitrate. Further, a thin filmcomposed of a cellulose-based resin blended or mixed with othercomponents (resin, plasticizer, cross-linker, etc.) can also be used asthe cellulose-based resin film, as long as a main component is thecellulose-based resin, and a serious damage to the administrationcharacteristics (administration efficiency, biological compatibility,safety, etc.) of a drug, which impairs the use as an iontophoresisdevice, is not caused.

Furthermore, the cellulose-based resin film may be a porous film with anappropriate pore size in accordance with the molecular weight of drugions to be administered. The average pore diameter is typicallyapproximately 1 Å to several μm, and it may be preferable to have a poresize of approximately 1 to 1,000 Å, and or approximately 1 to 100 Å.

In another aspect, the iontophoresis device uses the active electrodestructure under the condition that it is attached to the biologicalinterface of a living body. Therefore, it is desired that thecellulose-based resin film used herein have flexibility capable offollowing the expansion/contraction and bending of the biologicalinterface of the living body and a strength to such a degree not to bebroken with a stress caused by such expansion/contraction and bending.Generally, when the thickness of the cellulose-based resin filmincreases, the strength can be enhanced, while the flexibility isreduced. Therefore, it is preferable that an appropriate thickness beselected in conjunction with the above-mentioned both characteristics inaccordance with the kind of the cellulose-based resin film.

In a further aspect, the cellulose-based resin film can incorporate acation exchange group such as a sulfonic acid group, a carboxylic acidgroup, or a phosphonic acid group by the action of chlorosulfonic acid,chloracetic acid, an inorganic cyclic triphosphate, or the like. Thiscan further enhance the transport number of drug ions in theadministration of a drug, and further enhance the administrationefficiency of a drug.

In yet a further aspect, a cellulose-based resin film filled withion-exchange resin with a cation exchange group introduced thereto canalso be used as the cellulose-based resin film. This also may enhancethe transport number of drug ions in the administration of a drug, andfurther increases the administration efficiency of a drug.

Such a cellulose-based resin film can, for example, be obtained by:impregnating a porous thin film body composed of cellulose-based resinwith a monomer composition composed of a hydrocarbon type monomer havinga function group capable of introducing a cation exchange group, across-linkable monomer, and a polymerization initiator; and allowingchlorosulfonic acid, chloracetic acid, an inorganic cyclic triphosphate,etc. to act on the resultant porous thin film body.

A sulfonic acid group that is a strong acid group is may be preferableas the cation exchange group to be introduced to the above-mentionedcellulose-based resin film or ion-exchange resin.

Furthermore, each of the above cation exchange groups may be present asa free acid, or may be present as a salt with alkaline metal ions suchas sodium ions and potassium ions, ammonium ions, etc.

In still another aspect, an iontophoresis device may comprise an activeelectrode structure having: an electrode to which a positive electricalpotential or voltage is applied; a drug holding part for holding a drugsolution containing positively charged drug ions, the drug holding partbeing placed on a front side of the electrode; and a complex filmcomposed of a cation exchange membrane and a cellulose-based resin filmplaced on a front side of the cation exchange membrane, the complex filmbeing placed on a front side of the drug holding part, in which the drugions are administered through the cellulose-based resin film. This mayfurther enhance the transport number in the administration of a drug,and further enhance the administration efficiency of a drug.

The complex film as mentioned above can also be used as thecellulose-based resin film of the previously described embodiments.

In this case, it may be preferable to use as the cation exchangemembrane a configuration filled with an ion-exchange resin in which acation exchange group is introduced to a porous film made of a materialsuch as polyolefin, a vinyl chloride resin, or a fluorine resin. Thismay further enhance the transport number in the administration of adrug.

In the above-mentioned complex film, in order to prevent an air layerfrom being present at an interface between the cation exchange membraneand the cellulose-based resin film, it may be preferable to bond theinterface between them so as to integrate the cation exchange membraneand the cellulose-based resin film.

Examples of a bonding method include adhesion by heat sealing,ultrasonic bonding, adhesion with an adhesive such as acyanoacrylate-type adhesive, and a cross-linking reaction with across-linker such as divinylbenzene. Alternatively, a cellulose-basedresin film is formed on a cation exchange membrane (e.g., cellulose isregenerated by allowing sulfuric acid to act on a cellulose copperammonia solution applied to a cation exchange membrane), whereby thecation exchange membrane can be bonded to the cellulose-based resinfilm.

Herein, in the case of bonding the cation exchange membrane to thecellulose-based resin film by the adhesion, cross-linking reaction, orformation of a cellulose-based resin film on a cation exchange membrane,it may be preferable to perform bonding under the condition that atleast the surface of a cation exchange membrane facing thecellulose-based resin film is roughened by an approach such asembossing, grooving, notching, mechanical polishing, or chemicalpolishing. This may enhance the adhesion and integration of the cationexchange membrane and the cellulose-based resin film.

Furthermore, the cation exchange membrane can also be roughened bymixing an inorganic filler such as calcium carbonate or magnesiumcarbonate, or an organic filler such as denatured polyethylene particlesor denatured polyacrylic acid resin particles, with a resin filmconstituting the cation exchange membrane.

BRIEF DESCRIPTION OF THE SEVERAL VIEWS OF THE DRAWINGS

In the drawings, identical reference numbers identify similar elementsor acts. The sizes and relative positions of elements in the drawingsare not necessarily drawn to scale. For example, the shapes of variouselements and angles are not drawn to scale, and some of these elementsare arbitrarily enlarged and positioned to improve drawing legibility.Further, the particular shapes of the elements as drawn, are notintended to convey any information regarding the actual shape of theparticular elements, and have been solely selected for ease ofrecognition in the drawings.

In the accompanying drawings:

FIG. 1 is a schematic diagram showing a configuration of aniontophoresis device according to one illustrated embodiment.

FIG. 2 is a schematic diagram showing a configuration of aniontophoresis device according to another illustrated embodiment.

FIG. 3A is a graph showing a time transition of the concentration ofmorphine in the blood before and after the administration of a drug,when morphine hydrochloride is administered to a mouse using theiontophoresis device according to one illustrated embodiment.

FIG. 3B is a chart showing a pH value (b) of a drug solution and anelectrolyte solution before and after the administration of a drug, whenmorphine hydrochloride is administered to a mouse using theiontophoresis device according to one illustrated embodiment.

FIG. 4 is a graph showing a time transition of the concentration ofmorphine in the blood, when morphine hydrochloride is administered to amouse using a conventional iontophoresis device.

FIG. 5 is a schematic diagram showing a configuration of a test deviceused for evaluating morphine transfer characteristics in vitro.

FIG. 6 is a graph showing evaluation results of morphine transfercharacteristics in a test device equivalent to the iontophoresis devicedisclosed herein.

FIG. 7 is a graph showing evaluation results of morphine transfercharacteristics in a test device equivalent to a conventionaliontophoresis device.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

In the following description, certain specific details are set forth inorder to provide a thorough understanding of various disclosedembodiments. However, one skilled in the relevant art will recognizethat embodiments may be practiced without one or more of these specificdetails, or with other methods, components, materials, etc. In otherinstances, well-known structures associated with iontophoresis devices,ion exchange membranes, power sources, voltage and/or current regulatorsand controllers have not been shown or described in detail to avoidunnecessarily obscuring descriptions of the embodiments.

Unless the context requires otherwise, throughout the specification andclaims which follow, the word “comprise” and variations thereof, suchas, “comprises” and “comprising” are to be construed in an open,inclusive sense, that is as “including, but not limited to.”

Reference throughout this specification to “one embodiment” or “anembodiment” means that a particular feature, structure or characteristicdescribed in connection with the embodiment is included in at least oneembodiment. Thus, the appearances of the phrases “in one embodiment” or“in an embodiment” in various places throughout this specification arenot necessarily all referring to the same embodiment. Further more, theparticular features, structures, or characteristics may be combined inany suitable manner in one or more embodiments.

The headings provided herein are for convenience only and do notinterpret the scope or meaning of the embodiments.

FIG. 1 shows an iontophoresis device X1, including an active electrodestructure 1, a counter electrode structure 2, and a power source 3, asmain components (members). Reference numeral 4 denotes a biologicalinterface such as skin or a mucous membrane.

The active electrode structure 1 includes an electrode 11 electricallycoupleable to a positive pole of the power source 3, an electrolytesolution holding part 12 for holding an electrolyte solution in contactwith or proximate the electrode 11, an anion exchange membrane 13 placedon a front side of the electrolyte solution holding part 12, a drugholding part 14 placed on a front side of the anion exchange membrane13, and a cellulose-based resin film 15 placed on a front side of thedrug holding part 14. The entire active electrode structure 1 is housedin a cover or a container 16 composed of a material, for example, aresin film or a plastic.

On the other hand, the counter electrode structure 2 includes anelectrode 21 connected to a negative pole of the power source 3, anelectrolyte solution holding part 22 for holding an electrolyte solutionin contact with or proximate the electrode 21, a cation exchangemembrane 23 placed on a front side of the electrolyte solution holdingpart 22, an electrolyte solution holding part 24 placed on a front sideof the cation exchange membrane 23, and an anion exchange membrane 25placed on a front side of the electrolyte solution holding part 24. Theentire counter electrode structure 2 is housed in a cover or a container26 composed of a material, for example, a resin film or a plastic.

In the iontophoresis device X1, those which are made of any conductivematerial can be used as the electrodes 11 and 21 without any particularlimit. In particular, a counter electrode composed of carbon, platinum,or the like may be preferred, and a carbon electrode free from theelution of metal ions and the transfer thereof to a living body may bemore preferred.

However, an active electrode such as a silver/silver chloride coupleelectrode in which the electrode 11 is made of silver and the electrode21 is made of silver chloride can also be adopted.

For example, in the case of using the silver/silver chloride coupleelectrode, in the electrode 11 that is a positive pole, a silverelectrode and chlorine ions (Cl⁻) easily react with each other togenerate insoluble AgCl as represented by Ag⁺Cl⁻→AgCl+e⁻, and in theelectrode 21 that is a negative pole, chlorine ions (Cl⁻) are elutedfrom a silver chloride electrode. Consequently, the following effectsmay be obtained: the electrolysis of water is suppressed, and the rapidacidification based on H⁺ ions at the positive pole, and the rapidbasification based on OH⁻ ions at the negative pole can be prevented.

In contrast, in the active electrode structure 1 and the counterelectrode structure 2 in the iontophoresis device X1 in FIG. 1, owing tothe function of the anion exchange membrane 13 and the cation exchangemembrane 23, the rapid acidification based on H⁺ ions in the electrolytesolution holding part 12 and the rapid basification based on OH⁻ ions inthe electrolyte solution holding part 22 may be suppressed. Therefore,an inexpensive carbon electrode free from the elution of metal ions canbe advantageously used in place of the active electrode such as asilver/silver chloride couple electrode.

Furthermore, the electrolyte solution holding parts 12, 22, and 24 inthe iontophoresis device X1 in FIG. 1 hold an electrolyte solution so asto maintain the conductivity. Phosphate buffered saline, physiologicalsaline, etc. can be used as the electrolyte solution typically.

Furthermore, in order to more effectively prevent the generation of gascaused by the electrolytic reaction of water and the increase in aconductive resistance caused by the generation of gas, or the change inpH caused by the electrolytic reaction of water, an electrolyte that ismore readily oxidized or reduced (i.e., oxidation at the positive poleand the reduction at the negative pole) than the electrolytic reactionof water can be added to the electrolyte solution holding parts 12 and22. In terms of the biological safety and economic efficiency (e.g., lowcost and easy availability), for example, an inorganic compound such asferrous sulfate or ferric sulfate, a medical agent such as ascorbic acid(vitamin C) or sodium ascorbate, and an organic acid such as lacticacid, oxalic acid, malic acid, succinic acid, or fumaric acid and/or asalt thereof may be preferred. Alternatively, a combination of thosesubstances (for example, 1:1 mixed aqueous solution containing 1 mol (M)of lactic acid and 1 mol (M) of sodium fumarate) can also be used.

The electrolyte solution holding parts 12, 22, and 24 may hold theabove-mentioned electrolyte solution in a liquid state. However, theelectrolyte solution holding parts 12, 22, and 24 may be configured byimpregnating a water-absorbing thin film carrier made of a polymermaterial or the like with the above-mentioned electrolyte solution,thereby enhancing the ease of handling thereof. The same thin filmcarrier as that can be used in the drug holding part 14 can be used asthe thin film carrier described herein. Therefore, the detail thereofwill be described in the following description regarding the drugholding part 14.

The drug holding part 14 in the iontophoresis device X1 according tothis embodiment holds at least an aqueous solution of a drug whoseactive ingredient is dissociated to positive drug ions by thedissolution, as a drug solution.

Herein, the drug holding part 14 may hold a drug solution in a liquidstate. However, it is also possible to impregnate such a water-absorbingthin film carrier as described below with a drug solution so as toenhance the ease of handling thereof.

Examples of a material that can be used for the water-absorbing thinfilm carrier in this case include a hydrogel body of acrylic resin(acrylhydrogel film), segmented polyurethane gel film, and/or an ionconductive porous sheet for forming a gel solid electrolyte. Byimpregnating the above aqueous solution at an impregnation ratio of 20to 60%, a high transport number (high drug delivery property), e.g., 70to 80% may be obtained.

The impregnation ratio in the present specification is represented by %by weight (i.e., 100×(W−D)/D[%] where D is a weight in a dry state and Wis a weight after impregnation). The impregnation ratio should bemeasured immediately after the impregnation with an aqueous solution toeliminate a chronological influence.

Furthermore, the transport number refers to the ratio of the amount ofcurrent contributing to the transfer of particular ions among the wholecurrent flowing through the electrolyte solution. In the presentspecification, the transport number is used in terms of that regardingdrug ions, i.e., the ratio of a current contributing to the transfer ofdrug ions among the whole currents supplied to the active electrodestructure.

Herein, the above-mentioned acrylhydrogel film (for example, availablefrom Sun Contact Lens Co., Ltd.) is a gel body having athree-dimensional network structure (i.e., cross-linking structure).When an electrolyte solution that is a dispersion medium is added to theacrylhydrogel film, the acrylhydrogel film becomes a polymer adsorbenthaving ion conductivity. Furthermore, the relationship between theimpregnation ratio of the acrylhydrogel film and the transport numbercan be adjusted by controlling the size of the three-dimensional networkstructure and the kind and ratio of a monomer constituting a resin. Theacrylhydrogel film with an impregnation ratio of 30 to 40% and atransport number of 70 to 80% can be prepared from2-hydroxyethylmethacrylate and ethyleneglycol dimethacrylate (monomerratio 98 to 99.5:0.5 to 2), and it is confirmed that the impregnationratio and transport number are almost the same in a range of an ordinarythickness of 0.1 to 1 mm.

Furthermore, the segmented polyurethane gel film has, as segments,polyethylene glycol (PEG) and polypropylene glycol (PPG), and can besynthesized from a monomer and diisocyanate constituting these segments.The segmented polyurethane gel film has a three-dimensional structurecross-linked by a urethane bond, and the impregnation ratio, transportnumber, and adhesion strength of the gel film can be easily adjusted bycontrolling the size of a network, and the kind and ratio of a monomerin the same way as in the acrylhydrogel film. When water that is adispersion medium and an electrolyte (alkaline metal salt, etc.) areadded to the segmented polyurethane gel film (porous gel film), oxygenin an ether connecting part of polyether forming a segment and analkaline metal salt form a complex, and ions of the metal salt move tooxygen in a subsequent blank ether connecting part when a current flows,whereby the conductivity is expressed.

As the ion conductive porous sheet for forming a gel solid electrolyte,for example, there is the one disclosed in JP 11-273452 A. This poroussheet is based on an acrylonitrile copolymer, and a porous polymer witha porosity of 20 to 80%. More specifically, this porous sheet is basedon an acrylonitrile copolymer with a porosity of 20 to 80% containing 50mol % or more (preferably 70 to 98 mol %) of acrylonitrile. Theacrylonitrile gel solid electrolytic sheet (solid-state battery) isprepared by impregnating an acrylonitrile copolymer sheet soluble in anon-aqueous solvent and having a porosity of 20 to 80%, with anon-aqueous solvent containing an electrolyte, followed by gelling, anda gel body includes a gel to a hard film.

In terms of the ion conductivity, safety, and the like, it may bepreferable to compose the acrylonitrile copolymer sheet soluble in anon-aqueous solvent of an acrylonitrile/C1 to C4 alkyl (meth)acrylatecopolymer, an acrylonitrile/vinylacetate copolymer, anacrylonitrile/styrene copolymer, an acrylonitrile/vinylidene chloridecopolymer, or the like. The copolymer sheet is made porous by anordinary method such as a wet (dry) paper making method, aneedlepunching method that is a kind of a non-woven fabric producingmethod, a water-jet method, drawing perforation of a melt-extrudedsheet, or perforation by solvent extraction. Among the above-mentionedion conductive porous sheets of an acrylonitrile copolymer used in asolid-state battery, a gel body (a gel to a hard film) holding theabove-mentioned aqueous solution in a three-dimensional network of apolymer chain and in which the above-mentioned impregnation ratio andtransport number are achieved is useful as a thin film carrier used inthe drug holding part 14 or the electrolyte solution holding parts 12,22, and 24.

Regarding the conditions for impregnating the above-mentioned thin filmcarrier with a drug solution or an electrolyte solution, the optimumconditions may be determined in terms of the impregnation amount,impregnation speed, and the like. For example, an impregnation conditionof 30 minutes at 40° C. may be selected.

An ion-exchange membrane carrying an ion-exchange resin having an anionexchange function in a base, for example, NEOSEPTA, AM-1, AM-3, AMX,AHA, ACH, ACS, ALE04-2, AIP-21, produced by Tokuyama Co., Ltd. can beused as the anion exchange membrane (ion-exchange membrane havingcharacteristics of selectively passing negative ions) 13 and 25 in theiontophoresis device X1 according to this embodiment. An ion-exchangemembrane carrying an ion-exchange resin having a cation exchangefunction in a base, for example, NEOSEPTA, CM-1, CM-2, CMX, CMS, CMB,CLE04-2, produced by Tokuyama Co., Ltd. can be used as the cationexchange membrane (ion-exchange membrane having characteristics ofselectively passing positive ions) 23. In particular, a cation exchangemembrane in which a part or an entirety of a pore of a porous film isfilled with an ion-exchange resin having a cation exchange function, oran anion exchange membrane filled with an ion-exchange resin having ananion exchange function can be used preferably.

Herein, a fluorine type resin with an ion-exchange group introduced to aperfluorocarbon skeleton or a hydrocarbon type resin containing a resinthat is not fluorinated as a skeleton can be used as the above-mentionedion-exchange resin. In view of the convenience of a production process,a hydrocarbon type ion-exchange resin is preferable. Furthermore,although the filling ratio of the ion-exchange resin is also related tothe porosity of the porous film, the filling ratio is generally 5 to 95%by mass, in particular, approximately 10 to 90% by mass, and may bepreferred to be approximately 20 to 60% by mass.

Furthermore, there is no particular limit to an ion-exchange group ofthe above-mentioned ion-exchange resin, as long as it is a functionalgroup generating a group having negative or positive charge in anaqueous solution. As specific examples of the functional group to besuch an ion-exchange group, those of a cation exchange group include asulfonic acid group, a carboxylic acid group, and a phosphonic acidgroup. Those acid groups may be present in the form of a free acid or asalt. Examples of a counter cation in the case of a salt includealkaline metal cations such as sodium ions and potassium ions, andammonium ions. Of those cation exchange groups, generally, a sulfonicacid group that is a strong acidic group is particularly preferable.Furthermore, examples of the anion exchange group include primary totertiary amino groups, a quaternary ammonium group, a pyridyl group, animidazole group, a quaternary pyridinium group, and a quaternaryimidazolium group. Examples of a counter anion in those anion exchangegroups include halogen ions such as chlorine ions and hydroxy ions. Ofthose anion exchange groups, generally, a quaternary ammonium group anda quaternary pyridinium group that are strong basic groups are usedpreferably.

Furthermore, a film shape or a sheet shape having a number of smallholes passing from front to back sides are used as the above-mentionedporous film without any particular limit. In order to satisfy both thehigh strength and the flexibility, the porous film may be made of athermoplastic resin.

Examples of the thermoplastic resins constituting the porous filminclude, without limitation: polyolefin resins such as homopolymers orcopolymers of α-olefins such as ethylene, propylene, 1-butene,1-pentene, 1-hexene, 3-methyl-1-butene, 4-methyl-1-pentene, and5-methyl-1-heptene; vinyl chloride resins such as polyvinyl chloride,vinyl chloride-vinyl acetate copolymers, vinyl chloride-vinylidenechloride copolymers, and vinyl chloride-olefin copolymers; fluorineresins such as polytetrafluoroethylene, polychlorotrifluoroethylene,polyvinylidene fluoride, tetrafluoroethylene-hexafluoropropylenecopolymers, tetrafluoroethylene-perfluoroalkyl vinylether copolymers,and tetrafluoroethylene-ethylene copolymers; polyamide resins such asnylon 6 and nylon 66; and those which are made from polyamide resins.Polyolefin resins may be preferable as they are superior in mechanicalstrength, flexibility, chemical stability, and chemical resistance, andhave good compatibility with ion-exchange resins. As the polyolefinresins, polyethylene and polypropylene may be particularly preferableand polyethylene may be most preferable.

There is no particular limit to the property of the above-mentionedporous film made of the thermoplastic resin. However, the average porediameter of pores of approximately 0.005 to 5.0 μm may be preferred,while approximately 0.01 to 2.0 μm may be more preferred, andapproximately 0.02 to 0.2 μm may be most preferred since the porous filmhaving such an average pore diameter is likely to be a thin ion-exchangemembrane having excellent strength and a low electric resistance. Theaverage pore diameter in the present specification refers to an averageflow pore diameter measured in accordance with a bubble point method(JIS K3832-1990). Similarly, the porosity of the porous film ofapproximately 20 to 95% may be preferred, while approximately 30 to 90%may be more preferred, and approximately 30 to 60% may be mostpreferred. Furthermore, the thickness of the porous film may ofapproximately 5 to 140 μm, approximately 10 to 120 μm may be even morepreferred, and approximately 15 to 55 μm may be most preferred. Usually,an anion exchange membrane or a cation exchange membrane using such aporous film has a thickness of the porous film with +0 to 20 μm.

The cellulose-based resin film 15 used in the iontophoresis device X1according to this embodiment can be constituted by cellulose-basedresins such as regenerated cellulose manufactured by a method such as acuprammonium process or a tertiary amineoxide process, cellulose esters(e.g., cellulose acetate, cellulose propionate, or cellulose acetatebutyrate), cellulose ethers (e.g., hydroxyethyl cellulose orhydroxypropyl cellulose) or nitrocellulose. A porous thin film ofcellulose-based resins having an average pore diameter of approximately1 Å to a few μm may be preferred, approximately 1 to 1,000 Å may be morepreferred, and around 1 to 100 Å may be particularly preferred, and athickness of approximately 10 to 200 μm may be preferred, andapproximately 20 to 50 μm may be particularly preferred.

A cation exchange group such as a sulfonic acid group, a carboxylic acidgroup, or a phosphonic acid group can be introduced to theabove-mentioned cellulose-based resin film by allowing chlorosulfonicacid, chloroacetic acid, inorganic cyclic triphosphate, or the like toact on the cellulose-based resin film. By using a cellulose-based resinfilm with such a cation exchange group introduced thereto as thecellulose-based resin film 15, the administration efficiency of a drugcan be enhanced further.

Alternatively, a porous thin film made of the above-mentionedcellulose-based resin in which pores are filled with a cation exchangeresin can also be used for the cellulose-based resin film 15.

The cellulose-based resin film filled with a cation exchange resin canbe obtained by: impregnating the above-mentioned porous thin film madeof a cellulose-based resin with a monomer composition composed of ahydrocarbon type monomer having a functional group capable ofintroducing a cation exchange group, a cross-linkable monomer, and apolymerization initiator; polymerizing them under appropriate reactionconditions; and allowing chlorosulfonic acid, chloracetic acid, aninorganic cyclic triphosphate, or the like to act on the resultantporous thin film.

Examples of the hydrocarbon-type monomer having a functional groupcapable of introducing a cation exchange group include aromatic vinylcompounds such as styrene, α-methylstyrene, 3-methylstyrene,4-methylstyrene, 2,4-dimethylstyrene, p-tert-butylstyrene, α-halogenatedstyrene, and vinylnaphthalene and each one or more of them can be used.Examples of an available cross-linkable monomer include: polyfunctionalvinyl compounds such as divinylbenzenes, divinyl sulfone, butadiene,chloroprene, divinylbiphenyl, and trivinylbenzene; and polyfunctionalmethacrylic acid derivatives such as trimethylol methanetrimethacrylate, methylenebis acrylamide, and hexamethylenemethacrylamide. Examples of an available polymerization initiatorinclude octanoyl peroxide, lauroyl peroxide,t-butylperoxy-2-ethylhexanoate, benzoyl peroxide, t-butylperoxyisobutyrate, t-butyl peroxylaurate, t-hexyl peroxybenzoate, anddi-t-butylperoxide.

In addition to the above components, other hydrocarbon-type monomerswhich are copolymerizable with the above hydrocarbon-type monomers andcross-linkable monomers, or plasticizers may be added as required.Examples of the other monomers which may be used include acrylonitrile,acrolein, and methylvinylketone. Further, examples of the plasticizerswhich may be used include dibutyl phthalate, dioctyl phthalate, dimethylisophthalate, dibutyladipate, triethylcitrate, acetyltributylcitrate,dibutylsebacate, and dibenzylether.

A battery, a voltage stabilizer, a current stabilizer (galvano device),a voltage/current stabilizer, or the like can be used as the powersource 3 in the iontophoresis device. It may be preferable to use acurrent stabilizer that is operated under safe voltage conditions inwhich an arbitrary current can be adjusted in a range of approximately0.01 to 1.0 mA, while approximately 0.01 to 0.5 mA, specifically, atapproximately 50V or less may be preferred and approximately 30 V orless may be even more preferred.

The iontophoresis device X1 according to this embodiment has remarkablyhigher administration efficiency of a drug than that of a conventionaliontophoresis device using a cation exchange membrane in place of thecellulose-based resin film 15, as described later in examples.

FIG. 2 illustrates a configuration of an iontophoresis device X2according to another embodiment.

As shown in FIG. 2, the iontophoresis device X2 has the sameconfiguration as that of the above-mentioned iontophoresis device X1,except that a complex film 17 made of a cation exchange membrane 17 aplaced on a front side of the drug holding part 14 and a cellulose-basedresin film 17 b placed on a front side of the cation exchange membrane17 a is provided, in place of the cellulose-based resin film 15.

The same cation exchange membrane as that described with respect to thecation exchange membrane 23 can be used as the cation exchange membrane17 a of the complex film 17. The same cellulose-based resin film as thatdescribed with respect to the cellulose-based resin film 15 can be usedas the cellulose-based resin film 17 b.

In order to prevent an air layer from being present at an interfacebetween the cation exchange membrane 17 a and the cellulose-based resinfilm 17 b, it may be preferable that the complex film 17 be formed bybonding the interface between the cation exchange membrane 17 a and thecellulose-based resin film 17 b by heat sealing, ultrasonic bonding,adhesion with an adhesive, chemical bonding with a cross-linker, orformation of the cellulose-based resin film 17 b on the cation exchangemembrane 17 a. In the case of bonding by means of the adhesion, chemicalbonding, or the like, in order to make the integration and adhesion ofthe bonding satisfactory, it may be preferable to use thecellulose-based resin film 17 b in which at least the connection sidesurface is roughened by an approach such as embossing, grooving,notching, mechanical polishing, or chemical polishing, or by mixing aninorganic filler such as calcium carbonate or magnesium carbonate and anorganic filler such as denatured polyethylene particles or denaturedpolyacrylic acid resin particles with a cellulose-based resin.

The condition of heat sealing and ultrasonic bonding, the kind andadhesion condition of an adhesive, the kind and cross-linking conditionof a cross-linker, and the like can be appropriately determineddepending upon the kind of the cation exchange membrane 17 a (mainly,the kind of a porous resin film used in the cation exchange membrane 17a) and the kind of the cellulose-based resin film 17 b. The connectionherein may prevent the administration efficiency of a drug fromdecreasing due to the presence of an air layer at the interface betweenthe cation exchange membrane 17 a and the cellulose-based resin film 17b. Therefore, the bonding should be sufficiently strong such that theinterface will not be peeled off due to the expansion/contraction andbending of the skin while the iontophoresis device is mounted.

In the iontophoresis device X2 according to this embodiment, theion-exchange ability of the complex film 17 is enhanced by the cationexchange membrane 17 a, so that the transport number in theadministration of a drug can be increased, and the administrationefficiency of a drug comparable to or higher than that of theiontophoresis device X1 can be obtained.

Example 1 In Vivo Test 1

Using a C57BL/6 mouse (male) of 20 to 24 weekly age as a test animal, anadministration test of morphine hydrochloride in the above-mentionediontophoresis device X1 was performed.

NEOSEPTA ALE04-2 produced by Tokuyama Co., Ltd. was used as each of theanion exchange membranes 13 and 25 of the iontophoresis device X1.NEOSEPTA CLE04-02 produced by Tokuyama Co., Ltd. was used as the cationexchange membrane 23. A regenerated cellulose dialysis membraneUC8-32-25 (average pore diameter: 50 Å, transmission molecular weight(MWCO): about 14,000, film thickness: 50 μm) of 99% α-cellulose obtainedfrom Viskase Sales Co. (Illinois in the US) was used as thecellulose-based resin film 15. 50 mg/mL of morphine hydrochloride wasused as a drug solution of the drug holding part 14. A 7:1 mixedsolution of 0.7 mol/L sodium fumarate aqueous solution and 0.7 mol/Llactic acid aqueous solution was used as an electrolyte solution of theelectrolyte solution holding parts 12, 22, and 24. The effective area ofthe active electrode structure 1 (area of a film surface of thecellulose-based resin film 15 through which a drug is administered (seethe reference S in FIG. 1) was 2.23 cm².

The drug was administered under the condition that the active electrodestructure 1 and the counter electrode structure 2 were brought intocontact with different sites of the shaved abdomen of the mouse, and aconstant current was allowed to flow continuously at 0.45 mA/cm² for 120minutes.

FIG. 3A shows the transition of the concentration of morphine in theblood of the mouse during the passage of a current under theabove-mentioned conditions, and FIG. 3B shows the pH values of theelectrolyte solution of the electrolyte solution holding parts 12, 22,and 24, and the drug solution of the drug holding part 14 before thecommencement of the passage of a current and after the completionthereof.

Comparative Example 1 In Vivo Test 2

Using an iontophoresis device with the same configuration as that of theiontophoresis device X1 of Example 1 except for using a cation exchangemembrane (NEOSEPTA CLE04-2 produced by Tokuyama Co., Ltd.) in place ofthe cellulose-based resin film 15, morphine hydrochloride wasadministered to the mouse under the same conditions as those of Example1.

Here, NEOSEPTA ALE04-2 that is an anion exchange membrane and CLE04-2that is a cation exchange membrane are ion-exchange membranes eachhaving a configuration in which a pore of a porous film is filled withan ion-exchange resin. Therefore the iontophoresis device used inComparative Example 1 has the same configuration as that of theiontophoresis device of JP 2004-188188 A that is considered to exhibitthe highest administration efficiency of a drug in the prior art.

FIG. 4 shows the transition of the concentration of morphine in theblood of the mouse during the passage of a current in ComparativeExample 1.

Reference Example 1 In Vitro Test 1

A test device having a configuration equivalent to that of theiontophoresis device X1 used in Example 1 was produced, and a constantcurrent was allowed to flow continuously at 0.45 mA/cm² for 120 minutes.

FIG. 5 illustrates the configuration of the test device. In FIG. 5,Reference numerals 11 and 21 denote electrodes. Reference numerals 13and 25 denote anion exchange membranes (i.e., NEOSEPTA ALE04-2 producedby Tokuyama Co., Ltd.). Reference numeral 23 denotes a cation exchangemembrane (i.e., NEOSEPTA CLE04-2 produced by Tokuyama Co., Ltd.).Reference numeral 15 denotes a cellulose-based resin film (i.e.,dialysis membrane UC8-32-25 produced by Viskase Sales Co.). Referencenumeral 4 denotes the skin collected from a mouse. An A-chamber, aD-chamber and an E-chamber are filled with a mixed solution (7:1) of 0.7mol/L sodium fumarate aqueous solution and 0.7 mol/L lactic acid aqueoussolution as an electrolyte solution. A B-chamber is filled with 50 mg/mLof morphine hydrochloride as a drug solution. A C-chamber is filled withphysiological saline.

FIG. 6 shows the transition of the concentration of morphine in theC-chamber during the passage of a current in Reference Example 1.

Comparative Reference Example 1 In Vitro Test 2

Using the same test device as that of Reference Example 1 except forusing a cation exchange membrane (i.e., NEOSEPTA CLE04-2 produced byTokuyama Co., Ltd.) in place of the cellulose-based resin film 15 inFIG. 5, which has an equivalent configuration to the iontophoresisdevice used in Comparative Example 1, a constant current was allowed toflow continuously at 0.45 mA/cm² for 120 minutes.

FIG. 7 shows the transition of the concentration of morphine in theC-chamber during the passage of a current in Comparative ReferenceExample 1.

As is apparent from the comparison between FIG. 3A and FIG. 4, theiontophoresis device, employing the cellulose-based resin film 15, mayadminister morphine at efficiency of approximately 5 to 10 times ormore, even as compared with the iontophoresis device having theconfiguration of Comparative Example 1 in which the administrationefficiency of a drug has been conventionally considered to be highest.

Furthermore, as shown in FIG. 3B, in the electrolyte solution in theelectrolyte solution holding parts 12, 22, and 24 and the drug solutionof the drug holding part 14 of the iontophoresis device, employing thecellulose-based resin film 15, the pH values hardly changed before andafter the passage of a current. Thus, it is understood that thebiological compatibility, safety and stability of the administration ofa drug may be ensured.

Furthermore, as shown in FIGS. 6 and 7, in the in vitro test, thetransfer speed of morphine in the test device (Reference Example 1) withthe cellulose-based resin film 15 was inferior by about tens ofpercentages to that of the test device (Comparative Reference Example 1)with the conventional configuration.

In the technical field of iontophoresis, the evaluation and study invitro are generally performed without using a living body in a stage ofselecting the material of a member of a device and the like. Asdescribed above, the effect of using a cellulose-based resin film canonly be confirmed by the evaluation in vivo, and can not be confirmed bythe evaluation in vitro, and this fact is considered to be a proof ofthe difficulty in constituting the present invention.

The present invention has been described with reference to theillustrated embodiments. The present invention is not limited thereto,and various alterations can be made within the scope of the claims.

For example, in the above embodiment, the case has been described wherethe active electrode structure includes the electrolyte solution holdingpart 12 and the anion exchange membrane 13, in addition to the electrode11, the drug holding part 14, and the cellulose-based resin film 15 (orthe complex film 17). However, the electrolyte solution holding part 12and the ion-exchange membrane 13 can also be omitted. In this case,although the function of suppressing the decomposition of a drug in thevicinity of the electrode 11, the movement of H⁺ ions to the skininterface, the function of suppressing the variation in pH at the skininterface caused by the movement of H⁺ ions, and the like cannot beachieved to such a degree as that in the above-mentioned embodiment, theadministration efficiency of a drug to a living body may be achievedsimilarly, and such an iontophoresis device is also included in thescope of the present invention.

Similarly, regarding the counter electrode structure, the cationexchange membrane 23 and the electrolyte solution holding part 24, orthe anion exchange membrane 25 in addition to the cation exchangemembrane 23 and the electrolyte solution holding part 24 can be omitted.In this case, although the performance of suppressing the change in pHin a contact surface of the counter electrode structure 2 with respectto the skin 4 cannot be achieved to such a degree as that in theabove-mentioned embodiment, the administration efficiency of a drug to aliving body may be achieved similarly, and such an iontophoresis deviceis also included in the scope of the present invention.

Alternatively, it is also possible that the counter electrode structure2 is not provided in the iontophoresis device, and for example, underthe condition that the active electrode structure is brought intocontact with the biological interface of a living body and a part of theliving body is brought into contact with a ground such as an electricalcoupling to earth, a drug is administered by applying an electricalpotential or voltage to the active electrode structure. Such aniontophoresis device may also similarly enhance the administrationefficiency of a drug to a living body and is included in the scope ofthe present invention.

Furthermore, in the above embodiment, the case has been described wherethe active electrode structure, the counter electrode structure, and thepower source are configured separately. It is also possible that thoseelements are incorporated in a single casing or an entire deviceincorporating them is formed in a sheet shape or a patch shape, wherebythe handling thereof is enhanced, and such an iontophoresis device isalso included in the scope of the present invention.

All of the above U.S. patents, U.S. patent application publications,U.S. patent applications, foreign patents, foreign patent applicationsand non-patent publications referred to in this specification and/orlisted in the Application Data Sheet, are incorporated herein byreference, in their entirety.

From the foregoing it will be appreciated that, although specificembodiments of the invention have been described herein for purposes ofillustration, various modifications may be made without deviating fromthe spirit and scope of the invention. Accordingly, the invention is notlimited except as by the appended claims.

1. An iontophoresis device, comprising an active electrode structurecomprising: an electrode to which a positive electrical potential isapplied; a drug holding part for holding a drug solution containingpositively charged drug ions, the drug holding part being placed on afront side of the electrode; and a cellulose resin film selected fromthe group consisting of regenerated cellulose, cellulose ester,cellulose ether, and cellulose nitrate and placed on a front side of thedrug holding part, wherein the positively charged drug ions areadministered through the cellulose resin film.
 2. The iontophoresisdevice according to claim 1, wherein a cation exchange group isintroduced to the cellulose resin film.
 3. The iontophoresis deviceaccording to claim 1, wherein: the active electrode structure furthercomprising an electrolyte solution holding part for holding anelectrolyte solution in contact with the electrode, and an anionexchange membrane placed on a front side of the electrolyte solutionholding part; and the drug holding part is placed on a front side of theanion exchange membrane.
 4. The iontophoresis device according to claim3, further comprising a counter electrode structure, comprising: asecond electrode to which a negative electrical potential is applied; asecond electrolyte solution holding part for holding an electrolytesolution in contact with the second electrode; a second cation exchangemembrane placed on a front side of the second electrolyte solutionholding part; a third electrolyte solution holding part for holding anelectrolyte solution, the third electrolyte solution holding part beingplaced on a front side of the second cation exchange membrane; and asecond anion exchange membrane placed on a front side of the thirdelectrolyte solution holding part.